This proposal seeks to advance our understanding of the role of thalamocortical networks in the production of cognitive control behaviors, and specifically, to understand how this network is perturbed in schizophrenia, a psychiatric illness affecting about 1% of the population, to produce cognitive control deficits in the disease. Both the prefrontal cortex (PFC) and the mediodorsal nucleus of the thalamus (MD) have been implicated to play a role in cognitive control tasks that involve working memory and context processing, areas that are functionally disrupted in patients with schizophrenia. These experiments will investigate how the thalamocortical network linking the MD to the dorsolateral PFC operates to implement cognitive control by relating neural dynamics in this network to the selection of one out of several alternative responses to the same stimulus. The approach will combine large-scale neural recording, pharmacological manipulation of synaptic function, and computational modeling of synaptic interactions to investigate how communication between neurons in the thalamus and the PFC allows prefrontal networks to switch between alternative responses to the same stimulus. We will then manipulate synaptic function with an NMDA receptor antagonist, which induces the specific pattern of errors in cognitive control as is seen in patients with schizophrenia. This will allow us to relate changes in physiological dynamics of local PFC and MD-PFC network to the observed deficit in behavioral performance. We will achieve the following two objectives: (1) provide one of the best available functional dissections of the role of thalamocortical prefrontal networks in information processing, and (2) reveal how disruption of the function of these networks could lead to cognitive deficits that typify human neuropsychiatric disease. Additionally, the temporal and spatial resolution of the single cell recordings in the proposed experiments allow for the potential to complement data from imaging studies by revealing how information processing is disrupted at a cellular level in schizophrenia. Eventually, this work will pave the way for the development and testing of new therapeutics such as new drugs, neuromodulation interventions, and gene therapies.